The Effects of Oral Dipyridamole Treatment on the Innate Immune Response During Human Endotoxemia

• Hemodynamics [ Time Frame: 24 hours after LPS administration ] [ Designated as safety issue: No ]
  Continious heart rate and blood pressure measurement
• Sensitivity to norepinephrine [ Time Frame: 24 hrs after LPS administration ] [ Designated as safety issue: No ]
  Venous occlusion plethysmography
• Endothelial-dependent and independent vasorelaxation [ Time Frame: 24 hours after LPS administration ] [ Designated as safety issue: No ]
  Venous occlusion plethysmography
• Markers of endothelial damage and circulating endothelial cells [ Time Frame: 24 hrs after LPS administration ] [ Designated as safety issue: No ]
  circulating adhesion molecules (ICAM, VCAM, E-selectin, P-selectin) circulating endothelial cells
• Urinary excretion of markers of renal injury [ Time Frame: 24 hrs after LPS administration ] [ Designated as safety issue: No ]
  GSTAlpha1-1 and GSTPi1-1
• Adenosine and related nucleotide concentrations [ Time Frame: 24 hrs after LPS administration ] [ Designated as safety issue: No ]
• Additional blood samples will be drawn for genetic testing and measurement of: mRNA and proteins part of the adenosine metabolism [ Time Frame: 24 hours after LPS administration ] [ Designated as safety issue: No ]
• Oxydative stress [ Time Frame: 24 hours after LPS administration ] [ Designated as safety issue: No ]
  Thiols, neutrophilic burst, calcium release of neuthrophils, TBARS, Carbonyls, FRAP, Myeloperoxidase, catalase, Griess assay

During sepsis and septic shock the immune response can be overwhelming leading to excessive tissue damage, organ failure and death. Ideally, the inflammatory response is modulated leading to both adequate protection to invading pathogens as well as limitation of an exuberant immune response. In the last few years adenosine is proposed to have a central role in the modulation of inflammation. In unfavorable conditions such as hypoxia, ischemia or inflammation adenosine is quickly up-regulated; with concentrations up to tenfold in septic patients. Many animal studies have shown that adenosine is able to attenuate the inflammatory response and decrease mortality rates. Therefore, pharmacological elevation of the adenosine concentration is an potential target to attenuate inflammation and limit organ injury. Dipyridamole, an adenosine re-uptake inhibitor is able to increase the adenosine concentration and limit ischemia-reperfusion injury. In order to study the effects of dipyridamole on the inflammatory response we aim to use the so called human endotoxemia model. This model permits elucidation of key players in the immune response to a gram negative stimulus in vivo, therefore serving as a useful tool to investigate potential novel therapeutic strategies in a standardized setting.

• Drug: Dipyridamole
  Oral treatment with dipyridamole 200 mg twice daily during seven consecutive days
  Other Name: Persantin retard
• Drug: Placebo
  Placebo twice daily during seven consecutive days
• Other: LPS
  The LPS derived from E. coli O:113 2ng/kg iv will be injected in 1 minute at a dosage of 2 ng/kg body weight.
  Other Name: Human endotoxemia

• Placebo Comparator: Endotoxemia placebo
  Endotoxin combined with placebo
  Interventions:

  • Drug: Placebo
  • Other: LPS
• Experimental: Endotoxemia Dipyridamole
  Endotoxin combined with Dipyridamol treatment
  Interventions:

  • Drug: Dipyridamole
  • Other: LPS

Inclusion Criteria:

• Age ≥ 18 and ≤ 35 years
• Male
• Healthy

Exclusion Criteria:

• Use of any medication.
• History of allergic reaction to dipyridamole
• Bleeding disorder.
• Smoking.
• Previous spontaneous vagal collapse.
• History, signs or symptoms of cardiovascular disease.
• Cardiac conduction abnormalities on the ECG consisting of a 2nd degree atrioventricular block or a complex bundle branch block.
• Hypertension (defined as RR systolic > 160 or RR diastolic > 90).
• Hypotension (defined as RR systolic < 100 or RR diastolic < 50).
• Renal impairment (defined as plasma creatinin >120 μmol/l).
• Liver enzyme abnormalities or positive hepatitis serology.
• Positive HIV serology or any other obvious disease associated with immune deficiency.
• Febrile illness in the week before the LPS challenge.
• Participation in another drug trial or donation of blood 3 months prior to the planned LPS challenge.